Chemical Properties of the Leinamycin-Guanine Adduct in DNA

The reaction of the antitumor agent leinamycin with thiols converts this natural product into an episulfonium ion that alkylates the N7-position of guanine residues in double-stranded DNA. It is reported here that depurination of this adduct is unusually facile, occurring with a half-life of about 3.5 h at pH 7 and 37°C in duplex DNA. This is one of the most rapid depurination reactions ever observed for an N7-alkylguanine residue. The rate constant for the depurination reaction was measured at several temperatures, and the activation parameters were calculated from the data. The energy of activation (E a ) for this reaction is 24.6 kcal/mol, and the Arrhenius A value is 1.2 × 10 13 s -1 . These values correspond to a ∆H ‡ ) 24.0 kcal/mol and ∆S ‡ ) -0.78 eu and are consistent with the expected unimolecular (D N + A N ) mechanism for the depurination reaction. Changes in ionic strength (0-500 mM NaCl) or pH (3-8) do not significantly alter the rate of depurination, and the base excision repair protein Aag, which removes a variety of N7-alkylguanine residues from duplex DNA, does not excise the leinamycin-guanine adduct. Possible biological implications of this rapid depurination process are considered. Finally, during the course of these studies, the release of hydrolyzed leinamycin (4; Scheme 1) from leinamycin-modified DNA was observed. This result suggests that leinamycin may be a reversible DNA alkylating agent

Structural subnetwork evolution across the life-span: rich-club, feeder, seeder

The impact of developmental and aging processes on brain connectivity and the connectome has been widely studied. Network theoretical measures and certain topological principles are computed from the entire brain, however there is a need to separate and understand the underlying subnetworks which contribute towards these observed holistic connectomic alterations. One organizational principle is the rich-club - a core subnetwork of brain regions that are strongly connected, forming a high-cost, high-capacity backbone that is critical for effective communication in the network. Investigations primarily focus on its alterations with disease and age. Here, we present a systematic analysis of not only the rich-club, but also other subnetworks derived from this backbone - namely feeder and seeder subnetworks. Our analysis is applied to structural connectomes in a normal cohort from a large, publicly available lifespan study. We demonstrate changes in rich-club membership with age alongside a shift in importance from 'peripheral' seeder to feeder subnetworks. Our results show a refinement within the rich-club structure (increase in transitivity and betweenness centrality), as well as increased efficiency in the feeder subnetwork and decreased measures of network integration and segregation in the seeder subnetwork. These results demonstrate the different developmental patterns when analyzing the connectome stratified according to its rich-club and the potential of utilizing this subnetwork analysis to reveal the evolution of brain architectural alterations across the life-span

A geometric network model of intrinsic grey-matter connectivity of the human brain

Network science provides a general framework for analysing the large-scale brain networks that naturally arise from modern neuroimaging studies, and a key goal in theoretical neuro- science is to understand the extent to which these neural architectures influence the dynamical processes they sustain. To date, brain network modelling has largely been conducted at the macroscale level (i.e. white-matter tracts), despite growing evidence of the role that local grey matter architecture plays in a variety of brain disorders. Here, we present a new model of intrinsic grey matter connectivity of the human connectome. Importantly, the new model incorporates detailed information on cortical geometry to construct ‘shortcuts’ through the thickness of the cortex, thus enabling spatially distant brain regions, as measured along the cortical surface, to communicate. Our study indicates that structures based on human brain surface information differ significantly, both in terms of their topological network characteristics and activity propagation properties, when compared against a variety of alternative geometries and generative algorithms. In particular, this might help explain histological patterns of grey matter connectivity, highlighting that observed connection distances may have arisen to maximise information processing ability, and that such gains are consistent with (and enhanced by) the presence of short-cut connections

Automated individual-level parcellation of Broca's region based on functional connectivity

Broca's region can be subdivided into its constituent areas 44 and 45 based on established differences in connectivity to superior temporal and inferior parietal regions. The current study builds on our previous work manually parcellating Broca's area on the individual-level by applying these anatomical criteria to functional connectivity data. Here we present an automated observer-independent and anatomy-informed parcellation pipeline with comparable precision to the manual labels at the individual-level. The method first extracts individualized connectivity templates of areas 44 and 45 by assigning to each surface vertex within the ventrolateral frontal cortex the partial correlation value of its functional connectivity to group-level templates of areas 44 and 45, accounting for other template connectivity patterns. To account for cross-subject variability in connectivity, the partial correlation procedure is then repeated using individual-level network templates, including individual-level connectivity from areas 44 and 45. Each node is finally labeled as area 44, 45, or neither, using a winner-take-all approach. The method also incorporates prior knowledge of anatomical location by weighting the results using spatial probability maps. The resulting area labels show a high degree of spatial overlap with the gold-standard manual labels, and group-average area maps are consistent with cytoarchitectonic probability maps of areas 44 and 45. To facilitate reproducibility and to demonstrate that the method can be applied to resting-state fMRI datasets with varying acquisition and preprocessing parameters, the labeling procedure is applied to two open-source datasets from the Human Connectome Project and the Nathan Kline Institute Rockland Sample. While the current study focuses on Broca's region, the method is adaptable to parcellate other cortical regions with distinct connectivity profiles

Synthesis of the distribution of subsidence of the lower Ganges-Brahmaputra Delta, Bangladesh

Deltas, the low-lying land at river mouths, are sensitive to the delicate balance between sea level rise, land subsidence and sedimentation. Bangladesh and the Ganges-Brahmaputra Delta (GBD) have been highlighted as a region at risk from sea-level rise, but reliable estimates of land subsidence have been limited. While early studies suggested high rates of relative sea-level rise, recent papers estimate more modest rates. Our objective is to better quantify the magnitude, spatial variability, and depth variation of sediment compaction and land subsidence in the lower GBD to better evaluate the processes controlling them and the pattern of relative sea level rise in this vulnerable region. We combine subsidence and compaction estimates from hand-drilled tube wells and historic sites (1–5 mm/y), GNSS and river gauges (4–8 mm/y) and RSET-MH and borehole vertical strainmeters (9–10 mm/y) in SW Bangladesh. The differences between the different types of measurements reflect the different timescales, spatial distribution and depth sensitivity of the different observations. Rates are lower for times >300y providing data on the timescale of compaction. We also observe differences related to the degree to which different devices measure shallow and deep subsidence. Higher values reflect a greater component of subsidence from young shallow deposits from soil compaction and organic matter degradation. Thus, we observe different rates for different environments and physical settings. These differences indicate that in planning adaptation for rising sea level, hard construction with a solid foundation may experience different subsidence rates than open fields or reclaimed land with recent natural or anthropogenic sedimentation. Significance statement: Land subsidence increases the impact of sea level rise. We combine six different types of measurements that examine land subsidence in coastal Bangladesh. The results show that causes of subsidence, including compaction of the sediments varies both spatially and with depth, and that compaction and organic matter degradation from young shallow deposits is a significant contribution to subsidence. This suggests that hard construction with a solid foundation, such as buildings and embankments, may experience a lower subsidence rates than open fields or reclaimed land with recent natural or anthropogenic sedimentation

Coupled Growth and Division of Model Protocell Membranes

The generation of synthetic forms of cellular life requires solutions to the problem of how biological processes such as cyclic growth and division could emerge from purely physical and chemical systems. Small unilamellar fatty acid vesicles grow when fed with fatty acid micelles and can be forced to divide by extrusion, but this artificial division process results in significant loss of protocell contents during each division cycle. Here we describe a simple and efficient pathway for model protocell membrane growth and division. The growth of large multilamellar fatty acid vesicles fed with fatty acid micelles, in a solution where solute permeation across the membranes is slow, results in the transformation of initially spherical vesicles into long thread-like vesicles, a process driven by the transient imbalance between surface area and volume growth. Modest shear forces are then sufficient to cause the thread-like vesicles to divide into multiple daughter vesicles without loss of internal contents. In an environment of gentle shear, protocell growth and division are thus coupled processes. We show that model protocells can proceed through multiple cycles of reproduction. Encapsulated RNA molecules, representing a primitive genome, are distributed to the daughter vesicles. Our observations bring us closer to the laboratory synthesis of a complete protocell consisting of a self-replicating genome and a self-replicating membrane compartment. In addition, the robustness and simplicity of this pathway suggests that similar processes might have occurred under the prebiotic conditions of the early Earth.Exobiology Program (U.S.) (Grant EXB02- 0031-0018)United States. National Aeronautics and Space Administration (Exobiology Program) (Grant EXB02-0031-0018)Howard Hughes Medical Institute (Investigator

Acquisition of a Unique Onshore/Offshore Geophysical and Geochemical Dataset in the Northern Malawi (Nyasa) Rift

The Study of Extension and maGmatism in Malawi aNd Tanzania (SEGMeNT) project acquired a comprehensive suite of geophysical and geochemical datasets across the northern Malawi (Nyasa) rift in the East Africa rift system. Onshore/offshore active and passive seismic data, long‐period and wideband magnetotelluric data, continuous Global Positioning System data, and geochemical samples were acquired between 2012 and 2016. This combination of data is intended to elucidate the sedimentary, crustal, and upper‐mantle architecture of the rift, patterns of active deformation, and the origin and age of rift‐related magmatism. A unique component of our program was the acquisition of seismic data in Lake Malawi, including seismic reflection, onshore/offshore wide‐angle seismic reflection/refraction, and broadband seismic data from lake‐bottom seismometers, a towed streamer, and a large towed air‐gun source

Geochemistry of lavas from the 2005–2006 eruption at the East Pacific Rise, 9°46′N–9°56′N : implications for ridge crest plumbing and decadal changes in magma chamber compositions

Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 11 (2010): Q05T09, doi:10.1029/2009GC002977.Detailed mapping, sampling, and geochemical analyses of lava flows erupted from an ∼18 km long section of the northern East Pacific Rise (EPR) from 9°46′N to 9°56′N during 2005–2006 provide unique data pertaining to the short-term thermochemical changes in a mid-ocean ridge magmatic system. The 2005–2006 lavas are typical normal mid-oceanic ridge basalt with strongly depleted incompatible trace element patterns with marked negative Sr and Eu/Eu* anomalies and are slightly more evolved than lavas erupted in 1991–1992 at the same location on the EPR. Spatial geochemical differences show that lavas from the northern and southern limits of the 2005–2006 eruption are more evolved than those erupted in the central portion of the fissure system. Similar spatial patterns observed in 1991–1992 lavas suggest geochemical gradients are preserved over decadal time scales. Products of northern axial and off-axis fissure eruptions are consistent with the eruption of cooler, more fractionated lavas that also record a parental melt component not observed in the main suite of 2005–2006 lavas. Radiogenic isotopic ratios for 2005–2006 lavas fall within larger isotopic fields defined for young axial lavas from 9°N to 10°N EPR, including those from the 1991–1992 eruption. Geochemical data from the 2005–2006 eruption are consistent with an invariable mantle source over the spatial extent of the eruption and petrogenetic processes (e.g., fractional crystallization and magma mixing) operating within the crystal mush zone and axial magma chamber (AMC) before and during the 13 year repose period. Geochemical modeling suggests that the 2005–2006 lavas represent differentiated residual liquids from the 1991–1992 eruption that were modified by melts added from deeper within the crust and that the eruption was not initiated by the injection of hotter, more primitive basalt directly into the AMC. Rather, the eruption was driven by AMC pressurization from persistent or episodic addition of more evolved magma from the crystal mush zone into the overlying subridge AMC during the period between the two eruptions. Heat balance calculations of a hydrothermally cooled AMC support this model and show that continual addition of melt from the mush zone was required to maintain a sizable AMC over this time interval.This work has been supported by NSF grants OCE‐0525863 and OCE‐0732366 (D. J. Fornari and S. A. Soule), OCE‐0636469 (K. H. Rubin), and OCE‐ 0138088 (M. R. Perfit), as well as postdoctoral fellowship funds from the University of Florida